After months and months of work and input by doctors and researchers, Dr. Caroline Hastings at Children’s Hospital Research Center Oakland filed our second Investigational New Drug application (IND) with the FDA on July 14, 2010.

The 200+ page IND filing details our request to deliver hydroxy-propel-beta-cyclodextrin (HPBCD or CYCLO) directly into Addi and Cassi’s central nervous system and ultimately their brains.

Cassi and Addi adding good karma to the intrathecal cyclodextrin FDA filing

Addi and Cassi suffer from Niemann Pick Type C, a ultra rare and fatal genetic cholesterol disease that causes progressive neurological deterioration and has been callled the “childhood Alzheimer’s” as it causes dementia in children.

While only approximately 500 children in the world have double genetic defects on the Niemann Pick Type C gene, everyone is born with the NPC gene, and the gene regulates human cholesterol metabolism. Studying children like Addi and Cassi may lead to breakthroughs in more common diseases such as Alzheimer’s and heart disease where disrupted lipids and cholesterol are implicated.

For the past year, we have been treating Addi and Cassi with weekly intravenous infusions of cyclodextrin but we learned from leading blood brain barrier researchers that cyclodextrin does not readily cross from the bloodstream into the brain. However, when cyclodextrin is delivered directly into the brains of NPC animals (cats/mice), this compound is creating a remarkable effect and arresting the neurological condition.

Here is some data from the NIH and NINDS meeting last month from Dr. John Dietschy, one of world’s leading lipid and sterol researchers, at UT Southwestern. Dr. Dietschy’s data shows that cyclodextrin delivered into the central nervous system of NPC mice prevents neurodegeneration.

Niemann-Pick type C (NPC) disease is one of a number of disorders in which the underlying metabolic defect is abnormal accumulation of either cholesterol (C) or cholesteryl esters (CEs). The severity of the disease in organs like liver, lung, and CNS is proportional to the amount of sterol that accumulates in that particular tissue, and interventions that prevent this accumulation prevent the disease. Administration of cyclodextrin (CYCLO) rapidly overcomes the C transport defect seen in NPC1 and NPC2 disease and allows the sterol to move to the cytosolic compartment of cells, to be transported to the liver, and ultimately to be excreted from the body as bile acid. The ED50 for this effect equals ~300 mg/kg in most organs. However, the value in kidney, which is only ~30 mg/kg, is much higher in the CNS. The ED50 value for the lung is infinitely high. This ED50 value for the CNS is much lower when the CYCLO is administered directly into the brain. The acute or continuous administration of cyclodextrin into the CNS normalizes cholesterol metabolism and prevents neurodegeneration. To bring about these changes, the particular CYCLO must interact with C, but it need not bring about solubilization into the bulk-water phase. After administration of appropriate doses at appropriate intervals, the pools of C in nearly every organ are maintained at normal levels and disease is prevented. Only in lung is the abnormal C metabolism resistant to CYCLO therapy. Consequently, whereas liver and CNS disease can be prevented, pulmonary disease progresses.

Besides thanking Dr. Caroline Hastings, Dr. Ron Browne and Karen Barca for helping get this second IND submitted, there are countless others to thank for their generous assistance and strategic guidance:

NPC researcher Dr. Charles Vite worked closely with Dr. Steven Silber and the Johnson & Johnson team, who donated their time and critical expertise and knowledge to help conduct PK experiments on Addi and Cassi and the NPC cats

Alzheimer’s biomarker expert (Dr. Kaj Blennow) conducted important CSF biomarker experiments and has also offered to continue testing the twins’ CSF when we get approval from the FDA to move forward

Dr. Steve Walkley, Dr. John Dietschy, Dr. Jean Vance and Dr. David Begley provided critical research data on NPC animals in advance of publishing which helped accelerate this process

Dr. Joe Madsen in the department of neurosurgery at Children’s Boston and Dr. Peter Sun at CHRCO offered advice on the feasibility of delivering cyclodextrin into the CNS

Dr. Emil Kakkis, founder of BioMarin and the Kakkis EveryLife Foundation provided toxicity and safety advice as well as overall encouragement

Dr. Harrry Chugani at Children’s Hospital of Michigan provided cutting edge PET imaging which helped support our case to move in this new treatment direction

Countless others offered to read our protocol and provided a tip here and there which all adds up to a comprehensive FDA filing. We simply can’t thank all the people who donated their time to helping us make it this far.

The FDA apparently has 30 days to respond to our intrathecal cyclodextrin filing. We are praying that the FDA does not require unrealistic toxicity studies that we can’t afford or throws out some other hurdle that can’t be easily crossed. Addi and Cassi’s seizures are getting a lot worse and their disease is progressing with hypometabolsim spreading to many regions of their brains.

Intrathecal cyclodextrin treatment is our only hope to try and save their brains from dementia and save their lives.

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